Cells have a checkpoint mechanism in which, when the DNA therein is damaged, the cells temporarily arrest the cell cycle and repair the damaged DNA (Cell Proliferation, Vol. 33, pp. 261-274). In about a half of human cancers, a cancer suppressor gene, p53 is mutated or deleted and the cells thereby have lost the G1 checkpoint function thereof. However, such cancer cells still keep the G2 checkpoint function remaining therein, which is considered to be one factor of lowering the sensitivity of the cells to DNA-active anticancer agents and to radiations.
A Wee1 kinase is a tyrosine kinase that participates in the G2 checkpoint of a cell cycle. Wee1 phosphorylates Cdc2 (Cdk1) tyrosine-15 that participates in the progress to the M phase from the G2 phase in a cell cycle, thereby inactivating Cdc2 and temporarily arresting the cell cycle at the G2 phase (The EMBO Journal, Vol. 12, pp. 75-85). Accordingly, in cancer cells having lost the p53 function therein, it is considered that the G2 checkpoint function of Wee1 is important for repairing the damaged DNA so as to avoid the cell death. Heretofore, it has been reported that the reduction of Wee1 expression by RNA interference or the inhibition of Wee1 by a compound increases the sensitivity of cancer cells to adriamycin, X ray and gamma ray (Cancer Biology & Therapy, Vol. 3, pp. 305-313; or Cancer Research, Vol. 61, pp. 8211-8217). From the above, it is considered that a Wee1 inhibitor may inhibit the G2 checkpoint function of p53-deficient cancer cells, thereby increasing the sensitivity of the cells to DNA-active anticancer agents and to radiations.
As a low-molecular Wee1 kinase inhibitor, for example, compounds described in US Patent Application 2005/0250836 (Patent document 1), WO 2003/091255 (Patent document 2), Cancer Research, Vol. 61, pp. 8211-8217 (Non-patent document 1), Bioorg & Med. Chem. Lett., Vol. 15, pp. 1931-1935 (Non-patent document 2) and the like are known. However, the compounds described in these documents are completely different in structure from the compounds of the invention.
On the other hand, WO 99/61444 (Patent document 3) and WO 2004/041823 (Patent document 4) disclose compounds that partly have a relatively similar skeleton to that of the compounds of the invention. However, these documents do not at all disclose or suggest the compounds of the invention.